Saturday, 31 March 2012

A network of hundreds of interconnected and microscopically identifiable areas in the human cerebral cortex controls cognition, perception, and behaviour. Each area covers up to 40 square cm (40cm x 40cm) of the cortical (outside layer of the brain) surface and consists of up to 750 million nerve cells. The architecture which is the spatial distribution, number, size, and shape of nerve cells and their processes varies between different cortical areas of the brain. Nerve cells are interconnected within each area and with other brain regions and the spinal cord via fibre tracts, synapses, transmitters, modulators, and receptors. This incredible structural complexity underlies the functional organisation in the cerebral cortex.

The understanding of the driving forces and organizational principles of the human brain is a challenge by recent research suggests a unifying hierarchical and geometric rules behind the organizational details.

Surface area of the cerebral cortex is a highly heritable trait, yet little is known about genetic influences on regional cortical differentiation in humans. Using a data-driven, fuzzy clustering technique with magnetic resonance imaging data from 406 twins, we parceled cortical surface area into genetic subdivisions, creating a human brain atlas based solely on genetically informative data. Boundaries of the genetic divisions corresponded largely to meaningful structural and functional regions; however, the divisions represented previously undescribed phenotypes different from conventional (non–genetically based) parcellation systems. The genetic organization of cortical area was hierarchical, modular, and predominantly bilaterally symmetric across hemispheres. We also found that the results were consistent with human-specific regions being subdivisions of previously described, genetically based lobar regionalization patterns.

The structure of the brain as a product of morphogenesis (growth) is difficult to reconcile with the observed complexity of cerebral connectivity (connections of nerves in a network). We therefore analyzed relationships of adjacency (next to) and crossing between cerebral (brain) fibre pathways in four nonhuman primate (four different monkeys) species and in humans by using diffusion magnetic resonance imaging. The cerebral fibre pathways formed a rectilinear three-dimensional grid continuous with the three principal axes of development. Cortico-cortical pathways (pathways to the outermost layers of the brain in the grey matter) formed parallel sheets of interwoven paths in the longitudinal (longways) and medio-lateral (middle and side) axes, in which major pathways were local condensations. Cross-species homology was strong (most of the the pathways were similar in the different animals) and showed emergence of complex connectivity by continuous elaboration of this grid structure. This architecture naturally supports functional spatio-temporal (spacial and time effects) coherence, developmental path-finding, and incremental rewiring with correlated adaptation of structure and function in cerebral plasticity and evolution.

Nerve pathways in a monkey brain

For many years the brain has been thought to be a too complex of mesh of nerves like a spaghetti junction. However, just as the roads around Birmingham can be unravelled with a decent Sat Nav or map, so too have scientists unravelled the nerve pathways by imaging nerve tracts and by making 3D reconstructions. Rather than been a complex mess it seems that brain nerve networks is an orderly structure where brain pathways fit together in a curving grid. Rather than explaining all this in text you should just listen to the pod cast (click here) by the authors of this work to help explain this and then ask any questions. This suggests that the nerve tracts are made in simple grids during nerve development and these then curve as the structures grow and fold over and so simple structures can form complex structures as found in the human brains. Check out the human connectome project (click here) which aims to understand the human neural nework.

The importance of understanding the pathways of the brain is really going to help us understand how the brain works and to understand what happens when MS lesions occur in the brain, because these pathways are being interfered with. It will also help us to understand how the brain can compensate to blockage of certain pathways.

The association between common neuroradiological markers of multiple sclerosis (MS) and clinical disability is weak, a phenomenon known as the clinico-radiological paradox. Here, we investigated to which degree it is possible to predict individual disease profiles from conventional magnetic resonance imaging (MRI) using multivariate analysis algorithms. Specifically, we conducted cross-validated canonical correlation analyses to investigate the predictive information contained in conventional MRI data of 40 MS patients for the following clinical parameters: disease duration, motor disability (9-Hole Peg Test, Timed 25-Foot Walk Test), cognitive dysfunction (Paced Auditory Serial Addition Test), and the expanded disability status scale (EDSS). It turned out that the information in the spatial patterning of MRI data predicted the clinical scores with correlations of up to 0.80 (p < 10(-9)). Maximal predictive information for disease duration was identified in the precuneus and somatosensory cortex. Areas in the precuneus and precentral gyrus were maximally informative for motor disability. Cognitive dysfunction could best be predicted using data from the angular gyrus and superior parietal lobe. For EDSS, the inferior frontal gyrus was maximally informative. In conclusion, conventional MRI is highly predictive of clinical disability in MS when pattern-based algorithms are used for prediction. Thus, the so-called clinico-radiological paradox is not apparent when using suitable analysis techniques.

For many years there has been a disconnect between what the MRIers are seeing and what is happening neurologically to the MSers, for example beta interferon can be great at quelling some of the MRI lesions but this was not reflected by such marked clinical benefit in movement. This may have been not that surprising because the clinical feature is a product of effects within the spinal cord and the brain and so without taking the spinal cord into account, MRI of the brain may not be that great in predicting what occurs.

In addition MRI suffered and suffers from poor resolution in that it was not really sensitive enough to really tell us enough. Then there is the fantasy effect, whereby MRIers use the imaging of MS to ascribe the role of some imaging sequence to a pathological effect, without experimentally proving that their imaging events is actually detecting what is said to be detected. Do we really know what a T1 or T2 lesion is?, is gadolinium measuring inflammation? when it is more likely to be measuring fluid rather than cellular movement. As we have said before an r value of correlation of 0.5 or 0.6 is not really a correlation when a really good correlation is 1 (direct relation ship more of one means more of the other) or -1 (indirect relationship more of one means less of the other) and no correlation is near 0. In this study they get correlations up to 0.8 (not bad) and what they say if you look in certain areas of the brain, rather than globally and look every where, then you can better idea of what symptoms may occur. This is logical because damage to certain nerve circuits lead to certain symptoms so if you look in these areas it is not surprising that you can link the load of the lesions to certain symptoms.

BACKGROUND AND PURPOSE: Disruption of the BBB in MS is associated with the development of new lesions and clinical relapses and signifies the presence of active inflammation. It is most commonly detected as enhancement on MR imaging performed with contrast agents that are costly and occasionally toxic. We investigated whether the BBB status in white matter lesions may be indirectly ascertained via examination of features on T1- and T2-weighted images obtained before the injection of a contrast agent.

MATERIALS AND METHODS: We considered 93 brain MR imaging studies on 16 patients that included T1-, T2-, and T2-weighted FLAIR images and predicted voxel wise enhancement after intravenous injection of a gadolinium chelate. We then used these voxel-level predictions to determine the presence or absence of abnormal enhancement anywhere in the brain.

RESULTS: On a voxel-by-voxel basis, enhancement can be predicted by using contrast-free measures with an Area under the curve of 0.83 (95% CI, 0.80-0.87). At the whole-brain level, enhancement can be predicted with an area uder the curve of 0.72 (95% CI, 0.62-0.82).

CONCLUSIONS: In many cases, breakdown of the BBB in acute MS lesions may be inferred without the need to inject an MR imaging contrast agent. The inference relies on intrinsic properties of tissue damage in acute lesions. Although contrast studies are more accurate, they may sometimes be unnecessary.

The conclusion say it all, would you want the sort of right answer or the right answer? So it is worth having the the gadolinium-enhancing agent?

Methods: We conducted a genome-wide association study (GWAS) in 197 patients with PrMS and 234 controls of Italian origin. We tested the top 20 single nucleotide polymorphisms (SNPs) with suggestive evidence of association (p-value<10(-4)) in two independent sets of primary progressive MS cases and controls.

Results: We identified a risk-associated SNP in the HLA region in linkage disequilibrium (LD) with DRB1*1501 and DQB*0602 loci, with genome-wide significance (rs3129934(T), p(combined)=6.7×10(-16), OR=2.34, 95% CI=1.90-2.87), and a novel locus on chromosome 7q35 with suggestive evidence of association (rs996343(G), p(combined)=2.4×10(-5), OR=0.70, 95% CI=0.59-0.83) which maps within a human endogenous retroviral (HERV) element. Pathway analyses point to an expression regulation of genes involved in neurodegeneration, including glutamate metabolism (p<0.01) and axonal guidance signalling (p<0.02).

Conclusions: We have confirmed the established association with the HLA region and, despite the low statistical power of the study, we found suggestive evidence for association with a novel locus on chromosome 7, with a putative regulatory role.

We have known about a HLA link to MS for many years. This suggests that there is an immune effect somewhere influencing MS. There have been over 50 over genes, mostly immune associated, linked to the susceptibility to multiple sclerosis. These studies indicate that examining anything less than a few thousand samples generally does not tell us anything concrete. Therefore with less than 500 samples and only ~250 affected anything found in this study is probably dubious. The locus on chromosome 7 maps to HERV...."evidence for the Charcot Project?" They point to genes involved in neurodegeneration, is this because they think that progression links to neurodegeneration. Until more substantial studies are done we will not really know.

Conclusion: The association between MS disease and the MSRV-type HERV-W element now appears quite strong, as evidenced ex-vivo from serum and PBMC with post-mortem confirmation in brain lesions. Chronic progressive MS, RRMS and clinically isolated syndrome show different ELISA (Enzyme-Linked Immunosorbent Assay) and/or PCR profiles suggestive of an increase with disease evolution, and amplicon sequencing confirms the association with particular HERV-W elements.

HERV in an astrocyte

Thus there is now a bit more evidence to suggest that the Prof Gs may have something with HERV W the Charcot Project, (a plan to target EBV and HERV in MS) so now all they have to do is get that trial to deal with HERVs off the ground. It is interesting that other studies with a different HERV-FC found higher levels in RRMS than progressive MS.

Friday, 30 March 2012

Intrathecal synthesis of the antibodies specific to neurotrofic viruses: measles (M), rubella (R), Varicella-Zoster (Z), and/or H. simplex (H), known as "MRZH-reaction" plays important diagnostic role in multiple sclerosis (MS). Whereas the analysis of the oligoclonal IgG bands provides high sensitivity, the MRZH-reaction shows high specificity, and hence these methods complement each other. For the first time we applied multiplexing bead-based technology to simultaneously analyze cerebrospinal fluid (CSF) and serum concentrations of antibodies against these viruses, and to calculate the antibody specific indices (ASI's). The method shows reasonable precision: intra-assay, 2.9-6.7%, and inter-assay, 2.0-3.2%. The results are comparable with these obtained with other methods (ELISAs), including two runs of the certified external quality control schemes. Eighty-one percent of the MS cases (n=27) and none of the sex- and age-matched controls (n=14), except one subject with "borderline" anti-measles ASI of 1.5, showed intrathecal synthesis of IgG against at least one of the viruses discussed. The ratios of the MRZH-positive cases in the MS group were: 12/22 for M, 12/19 for R, 13/26 for Z, and 7/26 for H. We conclude that the multiplexing technology can be applied as a tool to study the intrathecal immune response in the diagnosis of MS.

Viruses have been associated as a trigger factor of MS, but it may not always be the same virus and so assaying form more than one at the same time may be a better idea than looking for one at a time. This study reports a way to look for evidence of past viral encounter by looking for antibodies in the brain-bathing fluid, the cerebrospinal fluid. This study found that about 80% had encountered at least one of four viruses compared to no healthy individuals. However we know that MS is associated with a leaky barrier that fails to stop white blood cells, including antibody producing cells, and antibody from entering the brain, so could that account for the elevated level of viral-specific antibody being detected in the brain or is it really disease related and what about Epstein Barr Virus.

Background: The ability of conventional MRI to predict subsequent physical disability and cognitive deterioration after a clinically isolated syndrome (CIS) is weak.

Objectives: This study investigated whether conventional MRI changes over 1 year could predict cognitive and physical disability 5 years later in CIS. The researchers performed analyses using a global approach (volume and number of lesions), but also a topographic approach (where the lesions were).

Methods: This study included 38 MSers with a CIS. At inclusion, 10 out of 38 MSers fulfilled the 2010 revised McDonald's criteria for the diagnosis of MS. EDSS evaluation was performed at baseline, year 1 and year 5, and cognitive evaluation at baseline and year 5. T(2)-weighted MRI was performed at baseline and year 1. They used voxelwise analysis (similar to pixels) to analyse the predictive value of lesions location for subsequent disability.

Results: Using the global approach, no correlation was found between MRI and clinical data. The occurrence or growth of new lesions in the brainstem (area of the brain linking the cerebral hemispheres to the spinal cord) was correlated with EDSS changes over the 5 years of follow-up. The occurrence or growth of new lesions in cerebellum, thalami, corpus callosum and frontal lobes over 1 year was correlated with cognitive impairment at 5 years.

Conclusion: The assessment of lesion location at the first stage of multiple sclerosis may be of value to predict future clinical disability.

"This study shows two things: (1) damage occurs early in MS; it is there at the CIS stage and progresses within the first 5-years. This is at a stage when most MSers don't look or feel disabled. The reason for this is that the brain copes and adapts to early damage. (2) the localization of MS lesions are important; lesion in the brainstem are more damaging than elsewhere. The brain-stem is a vital structure with a high-density of nerve fibres, so this result is not surprising. The natural conclusion of this study is that we should treat MS early and aggressively to stop new lesion formation and the sub-clinical accrual of damage that occurs with an increase in lesion volume and number early in the disease. Some people will argue against this strategy and will quote literature saying MRI activity does not correlate with disability. This may be true, but that is because these studies used conventional MRI. When you start looking at where the lesions develop, as in this study, the results are different. I strongly believe that we need to at least allow MSers the choice to have early aggressive treatment, despite the uncertainty about long-term outcomes. If MSers are well informed about MS and DMTS, including their potential benefits and risks, they are in the best position to decide for themselves. Not all MSers are risk-adverse, we need to realise that. If an MSer is risk adverse we also have to respect that position. There is no right or wrong; we need a personalised approach. "

Background: In a subgroup of MSers natalizumab therapy causes generation of anti-natalizumab antibodies that may be transient or persistent. It is recommended to discontinue natalizumab therapy in persistently antibody-positive patients.

Objective: To use titres of anti-natalizumab antibodies (NABs) to predict persistency of antibodies.

Patients and methods: In 525 consecutive natalizumab treated MSers tested for anti-natalizumab antibodies 43 (8.2%) were antibody-positive. Thirty of the antibody-positive MSers, who were tested both at three and at six months after treatment start, had antibody titres in blood measured.

Results: Samples from persistently positive MSers (N=18) had higher titre values than samples from transiently positive MSers (N=12). A cut-off value for high titre values was generated, above which patients may discontinue natalizumab therapy after three months. The method had a sensitivity of 0.83, a specificity of 1.00 and a diagnostic accuracy of 0.90.

Conclusion: Measuring anti-natalizumab antibody titres in MSers on natalizumab therapy may be used for evaluation of antibody persistence. A test at three months may identify MSers with high titres, who should discontinue natalizumab therapy, and MSers with transient low-titre antibodies, who may continue natalizumab therapy despite development of antibodies.

"If you are on natalizumab it is important to be screened for these antibodies. Recommendations are for screening to be done if you have an infusion reaction and routinely at 12 and 24 months. 75% of NAB positive MSers are likely to have infusion reactions, these typically occur on the 2nd, 3rd or 4th infusion. NABs to natalizumab stop the drug working; therefore NAB+ MSers' need to stop the drug and switch to another therapy. I am aware that not all treatment centres are routinely measuring these antibodies; they should be. If they are not they are not using natalizumab appropriately."

A dual role of B cells in experimental autoimmune encephalomyelitis (EAE), the animal model of the human autoimmune disease multiple sclerosis
(MS), has been established. In the first role, B cells contribute to
the pathogenesis of EAE through the production of anti-myelin antibodies
that contribute to demyelination. On the contrary, B cells have also
been shown to have protective functions in that they play an essential
role in the spontaneous recovery from EAE. In this review, we summarize
studies conducted in a number of species demonstrating the conditions
under which B cells are pathogenic in EAE. We also discuss the phenotype
and anti-inflammatory mechanisms of regulatory B cells.

This all well and good, but you need these reviews BEFORE the human trials are done. It has already been shown that rituximab and ocreluzimab (B cell blocking agents) can inhibit some aspects of MS whilst Atacicept another B cell blocking agent makes MS worse. My old Boss (John Leslie Turk) reported on B regulatory cells probably long before the above authors were born. That work was forgotten but the potential can come back to bite you in the a**e (a*s in American). Do anti B cell agents work by blocking anti-body production (immunologists view), but what about blocking antigen presentation function (alternative immunologist view) of if you are Prof B viral infection of B cells. It is again a case of the tail wagging the dog. The effects in EAE (speaking as an EAEer) are kind of irrelevant when we know what is going on in humans....but do we know what is going on? We need EAEers to change views before they they are shown to be wrong not after, otherwise it is just more and more bad science and importantly more false hopes for MSers.

An alternative hypothesis has been proposed implicating chronic cerebrospinal venous insufficiency (CCSVI) as a potential cause of multiple sclerosis (MS). We aimed to evaluate the validity of this hypothesis in a controlled animal model. Animal experiments were approved by the institutional animal care committee. The jugular veins in SJL mice were ligated bilaterally (n = 20), and the mice were observed for up to six months after ligation. Sham-operated mice (n = 15) and mice induced with experimental autoimmune encephalomyelitis (n = 8) were used as negative and positive controls, respectively. The animals were evaluated using CT venography and exametazime to assess for structural and haemodynamic changes. Imaging was performed to evaluate for signs of blood-brain barrier (BBB) breakdown and neuroinflammation. Flow cytometry and histopathology were performed to assess inflammatory cell populations and demyelination. There were both structural changes (stenosis, collaterals) in the jugular venous drainage and ahemodynamic disturbances in the brain on exametazime scintigraphy (p = 0.024). In the JVL mice, gadolinium MRI and immunofluorescence imaging for barrier molecules did not reveal evidence of BBB breakdown (p = 0.58). Myeloperoxidase, matrix metalloproteinase, and protease molecular imaging did not reveal signs of increased neuroinflammation (all p>0.05). Flow cytometry and histopathology also did not reveal increase in inflammatory cell infiltration or population shifts. No evidence of demyelination was found, and the mice remained without clinical signs. Despite the structural and haemodynamic changes, we did not identify changes in the BBB permeability, neuroinflammation, demyelination, or clinical signs in the JVL group compared to the sham group. Therefore, our murine (IT IS MOUSE!!!!!!! NOT MURINE THIS CAN MEAN RAT!!!!!-BOTH FROM THE GENUS MURIDAE.......YOU DON'T GET RATINE) model does not support CCSVI as a cause of demyelinating diseases such as multiple sclerosis.

I told you this was going to happen!!!! Ugh.........what's more this is no doubt the first one of more to follow.

Well it is official..... blocked jugular veins do not give you MS!!!!, because animals studies show this. You shout they did not not use the Zamboni ultrasound method to detect blockage!, but you can not get much more blocked than having the veins tied shut!. Where there any Dawsons fingers?.....Apparently Not!. Importantly there was no demyelination and no oligodendrocyte death before inflammation, because there was no inflammation!!

However, they could find inflammation and evidence of blood brain barrier disturbances in autoimmuniy, where you could see inflammation and demyelination.

So you put the idea that blocked veins cause, demyelinating disease forward...........and the hypothesis fails. The hypothesis has problems not because it fails in animals, but because it does not take into account the genetics and the aetiology of MS as well as treatment effects and other current knowledge of MS, but I do hope I am wrong and the trials are positive, just as I want all potential drugs to work.

Could this be wrong.....of course it could.

So you say animals do not get MS....well apparently not when they have blocked neck veins!!

Current evidence on the efficacy of percutaneous venoplasty for chronic cerebrospinal venous insufficiency (CCSVI) for multiple sclerosis (MS) is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research.

NICE encourages further research on percutaneous venoplasty for CCSVI for MS, in the form of robust controlled clinical trials. Studies should clearly define selection criteria and patient characteristics. They should also clearly define technical success which may include measurement of pressure gradients across treated vein segments before and after venoplasty. Outcomes should include clinical and quality of life measures.

"Spot on! I have been calling for this since the CCSVI issue arose. We need well designed clinical trials - not open labelled studies - but double-blind sham-controlled randomised studies. Nobody with MS should be paying for an unproven therapy. If you volunteer for trials it should be open and informed; you should sign a consent form. Even your travel costs should be covered. You should not be out of pocket. Don't forget this. There are too many Charlatans out there wanting to make money!"

Wednesday, 28 March 2012

"China has ordered a halt to all unapproved stem cell treatments and clinical trials, state media reported on Tuesday, as Beijing seeks to rein in the largely untested stem cell therapies now on offer across the country.

The Ministry of Health will stop accepting new applications for stem cell programs, a ban that will last until July and comes as China begins a one-year program to regulate the sector better, Xinhua cited a ministry spokesman as saying.

A growing number of hospitals and clinics in large cities in China have been offering stem cell therapies for treatment of diseases ranging from cancer and Alzheimer's to spinal cord injuries, treatments that are backed by little or no scientific evidence and which are considered at best experimental......."

"This is excellent news and will hopefully stop unproven stem cells therapies for MSers in China. I sincerely hope the rest of the world would adopt this policy as well. The only place for stem cell treatments for MS are within well-designed clinical trials. The Stem Cell Charlatans should be stopped; all the do is create false hope, rip MSers off and bring the filed into disrepute. The latter is a major problem for serious scientists working in the field."

"If previous years are anything to go by, most of the attendees will have progressive MS. I am therefore planning to focus on progressive MS and only briefly mention advance in the field of relapsing disease. What do you think?"

OBJECTIVE: To estimate the relative effectiveness of treatments in MS, we performed a network of multiple-treatments meta-analysis of randomized controlled trials (RCTs) for relapsing MS using three main efficacy outcomes: relapse-free patients, patients without disease progression, and patients without magnetic resonance imaging progression.

METHODS: We systematically searched PubMed and the Cochrane Central Register of Controlled Trials to identify English-language articles with RCTs that compared pharmaceutical treatments using the terms multiple sclerosis and randomized controlled trial. All RCTs that involved patients with definite relapsing MS and provided data for calculating the odds ratios for the main outcomes were considered. First, comparative effectiveness relative to placebo was assessed using direct analysis. Then, each therapy was compared with interferon beta-1b (250μg) in direct and indirect analyses. Effect sizes were estimated by applying a random-effects model.

RESULTS: We identified 4165 titles; after screening, 109 articles were eligible for inclusion. In total, 26,828 patients were included. The network consisted of 145 treatments involving 59 direct comparisons with placebo and 8 direct comparisons with interferon beta-1b (250μg). Two treatments showed better response compared with placebo (direct analysis) for all three efficacy outcomes: natalizumab (300mg) and fingolimod (0.5mg). In comparing treatments with interferon beta-1b (250μg), the network analysis revealed that no therapy shows better response for all 3 efficacy outcomes and alemtuzumab, 12 and 24 mg, have better response for 2 of the outcomes (relapse-free patients and patients without disease progression).

CONCLUSIONS: Although some treatments seem to have better efficacy, the results should be interpreted with caution because the network was dominated by indirect comparisons. Data from the selected studies included in the network cannot be extrapolated beyond them. Large RCTs that make head-to-head comparisons between treatments are needed to draw safe conclusions for the optimal treatment of MS.

"Did we need a meta-analysis to tell us that Natalizumab, Fingolimod and Alemtuzumab are more efficacious than interferon beta-1b and that glatiramer acetate and interferon beta-1a are similar in efficacy to interferon beta-1b? Almost certainly not!"

"The good news is that we are entering an era were will have access to therapies which are on average more effective than interferon beta and glatiramer acetate. I am sure that these treatments will make it easier for us to assess the impact on suppressing relapses on disease course. I have little doubt that MSers on these therapies will do better in the long-term."

MS is a demyelinating autoimmune disease of the central nervous system (CNS) with a presumed autoimmune etiology. Approved treatments for MS are immunoregulatory and are able to reduce the inflammatory components of the disease. However, these treatments do not suppress progressive clinical disability. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination are likely to improve long-term outcomes and reduce the rate of axonal damage. Galanin (GAL) is a bioactive neuropeptide that is widely distributed throughout the nervous system and has diverse neuromodulatory effects. In this study, using the cuprizone (CPZ) demyelination model of MS, we demonstrate that GAL has pronounced neuroprotective effects with respect to demyelination and remyelination. Using our GAL transgenic mouse (GAL-Tg), we identified a novel attenuation of OLs against CPZ induced demyelination, which was exerted independently of progenitor cells. Alleviation of myelin breakdown in the GAL-Tg mice was observed to be significant. Furthermore, we observed changes in the expression of the GAL receptor GalR1 during the demyelination and remyelination processes. Our data strongly indicate that GAL has the capacity to influence the outcome of primary insults that directly target OLs, as opposed to cases where immune activation is the primary pathogenic event. Taken together, these results suggest that GAL is a promising next-generation target for the treatment of MS.

Cuprizone is a toxin to certain oligodendrocytes in mice. This is yet another target for promoting repair. We had had a load of these new avenues, yet none have bourne fruit so far. This is encouraging as we have another way to modify this process.

OBJECTIVES: To determine whether there is a relationship between self-reported fatigue and the energy cost of walking (ECw), and how self-reported fatigue and ECw relate to physical functioning in patients with multiple sclerosis (MS).

PARTICIPANTS: MSers (N=75) were obtained from a longitudinal study on outcome measurement and functional prognosis in early MS. Patients were included if they were able to walk for 6 minutes without being assisted by a person. The age range was between 28.0 and 69.7 years and the median Expanded Disability Status Scale was 2.5 (range, 1.0-6.5).

MAIN OUTCOME MEASURES: Self-reported fatigue was measured with the Fatigue Severity Scale, the vitality subscale of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and a visual analog scale. Physical functioning was determined with the physical functioning subscale of the SF-36, fast walking speed, and comfortable walking speed. The ECw (J·kg(-1)·m(-1)) was measured with the energy cost of the walking test.

RESULTS: The relationship between ECw and latent variable fatigue had a β=-.188 (P=.236), that between ECw and physical functioning (SF-36 physical functioning) had a β=-.344 (P=.001), and that between fatigue and physical functioning had a β=-.448 (P=.000).

CONCLUSIONS: Fatigue and ECw are not related in patients with MS with mild to moderate walking problems. ECw and fatigue are independent determinants of physical functioning.

"MS-related fatigue, a percept, is not related to the energy cost of walking. A percept is a term we use as for the perception by the cortex of something in our external or internal environment. Fatigue is an important symptom and is usually a feedback mechanism to tell our bodies to take a rest. In MS this system goes awry; in MS there is a disconnect between what the brain perceives as fatigue and the energy requirements of performing a task such as walking. This confirms that fatigue is a complex symptom and will need to be tackled at multiple levels if we want to make a difference to MSers."

OBJECTIVE: To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon β-1a in early, active relapsing-remitting multiple sclerosis (RRMS). What are the long-term effects of alemtuzumab treatment, received 36 to 48 months previously, on relapse and disability in early, active RRMS? This study provides evidence of the effectiveness of alemtuzumab in reducing the relapse rate and accumulation of disability compared with interferon β-1a (IFNβ-1a) through extended follow-up (up to 60 months from baseline).

METHODS: Of 334 patients originally randomized, 198 participated in the extension phase (151 [68%] alemtuzumab and 47 [42%] IFNβ-1a). Disability, relapses, and safety were assessed as in the original study period. Efficacy outcomes were analyzed from baseline of the original trial period to 60 months. Safety data extended beyond 60 months.

RESULTS: Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% compared with IFNβ-1a (both p < 0.0001). The annualized relapse rate from baseline to month 60 was 0.11 for alemtuzumab and 0.35 for IFNβ-1a. Complete safety follow-up reflected 988 and 376 person-years for alemtuzumab and IFNβ-1a patients, respectively. Serious infections were seen in 7% of alemtuzumab patients and 3% of IFNβ-1a patients, and thyroid disorders were seen in 30% of alemtuzumab patients vs 4% of IFNβ-1a patients. Immune thrombocytopenia (autoimmune attack of platelets) occurred in 3% of alemtuzumab patients and 0.9% of IFNβ-1a patients during the initial study period; no additional events were reported during the extension phase. One alemtuzumab patient developed Goodpasture disease 39 months after the second annual cycle of alemtuzumab (This is a serious kidney problem often requiring tranplant).

CONCLUSIONS: Through extended follow-up, alemtuzumab remained significantly more efficacious than IFNβ-1a, with a safety profile consistent with previous reports.

We know that Alemtuzumab has more efficacy than beta interferon, but its use comes with significantly more side-effects. This increased efficacy maintains itself over many years.

Results: Interactions emerged between intellectual enrichment and group when predicting memory (p = 0.041) and cognitive efficiency (p = 0.024), such that SPMS patients exhibited deficits relative to HCs at lower levels of enrichment, but these SPMS-related cognitive deficits were absent at higher levels of enrichment.

I heard the sad news, on Friday, that Charles Fox passed away in Bolinas, California. Condolences to his daughter and family. I feel very sad. Plans were quite advanced for me and my family to take our summer holiday this year on the west coast of America; one of the objectives was to visit Charles in Bolinas. Sadly, this won't be possible now and I will have to add an item to my list of regrets. I should have made the effort to visit him earlier.

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The following is a re-posting; this post led to the survey and debate about should we or shouldn't we celebrate MS heroes?

I have just received, today, a signed version of a book by Charles Fox "With a Little Help from My Friends: A Love Story". Charles has had MS for over 30 years. I met him over the internet; he contacted me via email to ask me questions about Queen Square and the practice of neurology in the United Kingdom and specifically at the hospital where he was originally diagnosed.

I am very fortunate to have read most of the book already as single chapters that he has sent me over the past few years. Charles writes beautifully and his story is an amazing one. If you get the time it is an inspirational read. The book provides the sustenance and motivation to keep doing what we do; trying to conquer MS.

Whilst looking for his book on the web, I found this YouTube clip of him and Véro (apologies, it is a commercial but that is not the point).

In the acknowledgements he writes: "But, first and foremost, I thank my wife, Véro, for having sustained me long enough to get the job done and for giving me a happy ending."

I have been promising to visit Charles at his home in Bolinas (Northern California) for several years now; I need to get there sooner than later.

Multitemporal Association Tracking (MAT) is a new graph-based method for multitarget tracking in biological applications that reduces the error rate and implementation complexity compared to approaches based on bipartite matching. The data association problem is solved over a window of future detection data using a graph-based cost function that approximates the Bayesian a posteriori association probability. MAT has been applied to hundreds of image sequences, tracking organelle and vesicles to quantify the deficiencies in axonal transport that can accompany neurodegenerative disorders such as Huntington's Disease and Multiple Sclerosis and to quantify changes in transport in response to therapeutic interventions.

I know some of you say that our post sometimes go over your head, but there are also posts that go over my head. I haven't a clue what this report is really cacking-on about.. probably science fiction, but it serves as a reminder if you do not understand something, don't be a fraid to ask, there will be loads of people in the same boat.

BACKGROUND: Bowel dysfunction amongstmultiple sclerosis(MS) and spinal cord injury (SCI) patients often manifests as fecal (pooh) incontinence (FI) or constipation, but the pathophysiology is poorly understood. Anorectal physiology provides an objective assessment of lower bowel functions and is increasingly being used in clinical practice

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AIM:

The purpose of this study was to correlate symptoms of bowel dysfunction in patients with spinal cord disease with findings in anorectal physiology. We hypothesized that specific abnormalities will correlate with symptoms: prolonged recto-anal inhibitory reflex in patients with incontinence and decreased rectal mucosal blood flow in patients with constipation.

CONCLUSION:

Bowel symptoms in patients with MS and SCI correlate with specific alterations of anorectal physiology. This provides objective assessment of bowel symptoms and may allow tailored treatment to individual patients.

He has got his special lab coat in UK MS Society orange ready for "Meet the Scientists" when you will get the oppertunity to meet and talk with MS MouseDoc (back of lab coat in the inset) and his chums.

You can have your own Q & A session face to face, eyeball to eyeball, see them at the Meet the Scientists stand they should be easy to spot.........You set the agenda not us.

Saturday, 24 March 2012

"This is a very good question and is something neurologists have been grappling with for decades."

What is a relapse?

A relapse is defined as an episode of neurological symptoms that happens at least 30 days after any previous episode began, lasts at least 24 hours and is not attributable to another cause and occurs in the absence of an infection or fever.

In clinical trials the definition is more stringent and has to be accompanied by either new clinical signs, i.e. changes in the neurological examination, or an increase in the disability (EDSS) score. This is why you may hear the term "protocol defined relapse"; the "protocol" refers to the definition of a relapse that is used in that particular trial. To confuse things two clinical trials may use slightly different definitions of a relapse, which makes it hard to compare results from different trials.

Can relapses result in the appearance of old symptoms?

Yes. A relapse can result in the appearance of new symptoms, that you have not experienced before, or the recurrence or worsening of symptoms that have occurred in the past.

"What about intermittent symptoms?"

It is important not to confuse intermittent symptoms from a previous relapse with a new relapse. Intermittent symptoms occur when a damaged nerve pathway recovers, but the recovery is incomplete. The partially recovered nerves then become susceptible to heat and/or fatigue, which results in symptoms coming and going. For example, if you have previously had an episode of loss of vision or pins and needles you may find when you exercise, or get tired, or experience hot weather, your vision blurs or the pins and needles return. In this situation the symptoms usually resolve on rest or cooling and rarely last more than a few hours. This is not a relapse.

What causes a relapse?

A relapse is caused by an area of inflammation and demyelination (loss of the nerve's insulation) in a particular pathway in the brain an spinal cord. The pathological and MRI correlate of this is the so called MS lesion or MS plaque.

Are there other names for a relapse?

Yes. Relapses are also referred to as attacks, exacerbations, flare-ups, acute episodes or clinical events.

Here is a recently posted video on the state of CCSVI. It tells you where you can get your updates on the "fact" or "fiction" of the procedure and the state of play on how people are attempting to disprove the hypothesis in randomised blinded trials..............

Yes this is the basis of the Scientific (Karl Popper) approach....You should try to disprove your hypothesis (ideas) not prove it, when you can not disprove it, then you accept it and science moves forward.

If you think it rubbish or great you can comment on Youtube. I know you will say they did not all use the Prof Z protocol, but this really does not matter any more, as the trials are now in place. You should get an answer if venoplasty works or not. You don;t need more work to work out what to do you just need to repeate the reported succes, when in a controlled, blinded scenario.

I think this vidoe gives a fair view of the Scienfitifc Fraternity's approach. The Doc is not a neurologist so is he in the back pocket of pharma? Probably not.... You will say it is not fast enough as ever, but the process is being followed, as it is for every other drug. Until these blinded studies report things are unlikely to change much. Don't shoot the messenger.

PML Risk Infographic

Holistic Management of MS ver. 7.0

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